The main objective of this study is to elucidate the role of Notch3 signaling in the pathogenesis of ovarian cancer, one of the most lethal neoplastic diseases in women. It has been well-established that the Notch signaling is required during diverse developmental and physiological processes and aberration of the signaling pathway participates in cancer development. Based on our recent findings showing Notch3 gene amplification in ovarian cancers and its role in maintaining cell survival, we hypothesize that i) activation of Notch3 signaling pathway initiates tumor formation and/or propel tumor progression; ii) Pbx1, a Notch3-regulated gene, is responsible for the tumor-promoting phenotypes of Notch3 through its interaction with Hox proteins; iii) targeting the Notch3 signaling pathway has anti-tumor potential in cancer cells with active Notch signaling. To test the above hypotheses, we propose the following specific aims: Aim 1: Analyze the roles of Notch3 pathway activation in the development of ovarian carcinoma. Aim 2: Investigate the mechanism by which Pbx1 mediates tumor-promoting effects of Notch3 signaling. Aim 3: Assess anti- tumor potential of pharmacological targeting of the Notch3 pathway. The results from this study will address several critical questions centering the roles of Notch3 in cancer biology and should have implication for future development of Notch3-based target therapy. PUBLIC HEALTH RELEVANCE: The purpose of this study is to determine the molecular mechanism by which Notch3 pathway activation contributes to the development of ovarian cancer. Furthermore, we will delineate the role of a Notch3 target gene in modulating oncogenic phenotypes in ovarian cancer. We will test tumor suppressive effect using newly developed small molecules to block Notch3-Pbx1 pathway. The results from this study will further our understanding the molecular mechanisms in the tumorigenesis of ovarian cancer and will provide foundation for Notch3-based cancer therapy.